While improvements in diagnostic tools and therapies have led to decreased morbidity from heart disease, cancer and stroke (Jemal, A., Ward, E., Hao, Y. & Thun, M. Trends in the leading causes of death in the United States, 1970-2002. Jama 294, 1255-9, 2005), the epidemic of diabetes (Gerstein, H. C. & Waltman, L. Why don't pigs get diabetes? Explanations for variations in diabetes susceptibility in human populations living in a diabetogenic environment. Cmaj 174, 25-6 2006) and the aging population (Lane, N. E. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 194, S3-11 2006) are now posing a critical challenge for wound care. (Cavanagh, P. R., Lipsky, B. A., Bradbury, A. W. & Botek, G. Treatment for diabetic foot ulcers. Lancet 366, 1725-35 2005); (Falanga, V. Wound healing and its impairment in the diabetic foot. Lancet 366, 1736-43 2005). Frequent in this population is the use of anticoagulants. Also many wounds in their inflammatory state can have significant bleeding even in the presence of normal clotting parameters. Equipment and techniques for accelerating wound healing have critical in the care of these patients. The availability of device or system that would enhance both clotting and wound healing might would be a significant advance in treatment.
Suction has a long been a valuable tool in wound healing. The use of suction and related techniques in wound treatment has been well characterized in the literature. (See., e.g., Charikar and Jeter, Orringer, Wooding-Scott). Chest tubes, for example, re-approximate the parietal and visceral pleura while suction drains facilitate closure of large surgical spaces.
A recent improvement over suction alone in treating wounds has been the introduction of negative pressure or sub-atmospheric therapy systems as exemplified by the Vacuum Assisted Closure (VAC) systems of Argenta and Morykwas. (Argenta, L. C., Morykwas, M. J. Vacuum-assisted closure: a new method of wound control and treatment: clinical experience. Ann. Plast. Surg. 38: 563, 1997); (Morykwas, M. J., Argenta, L. C., Shelton-Brown, E. I., et al. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann. Plast. Surg. 38: 553, 1997); U.S. Pat. Nos. 5,636,643; 5,645,081). Argenta et al. found that the controlled distribution of pressure throughout the wound is important in speeding wound healing. In the original design the negative pressure was distributed over a mesh applied directly to the wound site.
The VAC system has become the preferred method in many centers for treating a wide array of complex wounds. In its current commercial embodiment the VAC is a system comprising a vacuum pump that delivers sub-atmospheric pressure to a polyurethane ether open pore foam (400-600 μm) covered by an occlusive polyurethane drape. It includes an open pore polyurethane foam in contact with the wound site, a semi-occlusive drape, and a suction tube in addition to the vacuum or suction pump. Several prospective studies have shown that the VAC system increases the healing of chronic wounds at least twice as rapidly as conventional methods such as wet to dry dressing changes. (Joseph, E., Hamori, C. A., Bergman, S., et al. A prospective randomized trail of vacuum-assisted closure versus standard therapy of chronic nonhealing wounds. Wounds 12: 60, 2000); (Edington, M. T., Brown, K. R., Seabrook, B. R., et al. A prospective randomized evaluation of negative pressure wound dressing for diabetic foot wounds. Ann. Vasc. Surg. 17: 645, 2003). Clinicians noted a rapid change in the wounds including overall shrinkage and induction of granulation tissue (Edington, M. T., Brown, K. R., Seabrook, B. R., et al. A prospective randomized evaluation of negative pressure wound dressing for diabetic foot wounds. Ann. Vasc. Surg. 17: 645, 2003); (Saxena, V., Hwang, C. W., Huang, S., et al. Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plast. Reconstr. Surg. 114: 1086, 2004).
Despite the commercial success of the device, it has certain limitations. One major limitation is that unless bleeding is completely stopped prior to use of the device, bleeding at the wound will continue or increase, often requiring removal of the VAC device. This has become particularly problematic given the increasing number of patients are on anticoagulants such as Coumadin, Heparin, Lovenox, Plavix and Aspirin. Having an effective method of obtaining hemostasis would be a great advantage to the VAC device in selected patients. Therefore a negative pressure wound device that incorporates hemostatic characteristics would be of great value to the wound care community.
There are many hemostatic agents currently on the market including micro-fibrillar collagen, oxidized regenerated cellulose, and lyophilized gelatin. Each of these agents can help with hemostasis, but in general, clinicians are reluctant to use these in many wounds because of the foreign body response that they can cause. Other methods such as fibrin glue are expensive and have at least a theoretical risk of viral transmission.
In addition, it would be preferable if the hemostatic agent used in such an application itself had a wound healing enhancing effect. Some hemostatic agents may provide control of hemorrhage and have a low foreign body response (as shown by favorable performance in an ISO implantation test) however it may have a negative wound healing effect. (E.g., Surgicel device manufactured by Ethicon, Inc.)
Therefore an appliance incorporating a hemostatic agent that could be incorporated into a negative pressure wound care device such as the VAC, that would also enhance (or at least not change) the efficacy of the device and would not induce significant foreign body response is highly desirable.
Highly homogeneous and pure poly-N-acetyl glucosamine (pGlcNAc) nanofibers can be isolated by the culture of a marine microalga. (Vournakis J N, Demcheva M, Whitson A, Guirca R, Pariser E R. Isolation, purification, and characterization of poly-N-acetyl glucosamine use as a hemostatic agent. J Trauma 2004, 57(1 Suppl):S2-6). pGlcNAc patches, which contain microalgal nanofibers (SyvekPatch™, Marine Polymer Technologies, Danvers, Mass.), have been characterized as hemostatic agents to control bleeding following catheter removal, and are currently used in interventional cardiology and radiology as non-invasive closure devices. (Vournakis J N, Demcheva M, Whitson A, Guirca R, Pariser E R. Isolation, purification, and characterization of poly-N-acetyl glucosamine use as a hemostatic agent. J. Trauma 2004, 57(1 Suppl):S2-6); (Najjar S F, Healey N A, Healey C M, McGarry T, Khan B, Thatte H S, et al. Evaluation of poly-N-acetyl glucosamine as a hemostatic agent in patients undergoing cardiac catheterization: a double-blind, randomized study. J Trauma 2004; 57(1 Suppl):538-41).
The N-acetyl glucosamine-containing oligo- and polysaccharides are an important class of glycosaminoglycans, molecules largely represented in the dermis and have superior wound healing properties. They are already used for inhibition of surgical adhesions, relief from joint pain, and for skin replacement in reconstructive surgery. (Fazio V W, Cohen Z, Fleshman J W, van Goor H, Bauer J J, Wolff B G, et al. Reduction in adhesive small-bowel obstruction by Seprafilm adhesion barrier after intestinal resection. Dis. Colon Rectum 2006; 49(1):1-11); Pena Ede L, Sala S, Rovira J C, Schmidt R F, Belmonte C. Elastoviscous substances with analgesic effects on joint pain reduce stretch-activated ion channel activity in vitro. Pain 2002, 99(3):501-8); Orgill D P, Straus F H, 2nd, Lee R C. The use of collagen-GAG membranes in reconstructive surgery. Ann N Y Acad. Sci. 1999; 888:233-48; Pietramaggiori, G., Yang, H., Scherer, S. S., Kaipainen, A., Chan, R. K., Alperovich, M., Newalder, J., Demcheva, M., Vournakis, J. N., Valeri, R. C., Hechtman, H. B., Orgill, D. P. Effects of poly-N-acetyl glucosamine (pGlcNAc) patch on wound healing in db/db mouse. J. Trauma (2008) 64(3):803-808; Vournakis, J., Eldridge, J., Demcheva M. and Muise-Helmericks, R. Poly-N-acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1. J. Vascular Res, (2008) 45:222-232.)
In addition, N-acetyl glucosamine is contained in chitosan, a polymer with demonstrated hemostatic properties. (Malette W G, Quigley H J, Gaines R D, Johnson N D, Rainer W G. Chitosan: a new hemostatic. Ann Thorac Surg 1983, 36(1):55-8). Although based on similar molecules, pGlcNAc and chitosan have structural, chemical, and biological differences; the former is constituted of highly ordered insoluble fibers, while the latter demonstrates a heterogeneous and soluble structure. (Fischer T H, Connolly R, Thatte H S, Schwaitzberg S S. Comparison of structural and hemostatic properties of the poly-N-acetyl glucosamine Syvek Patch with products containing chitosan. Microsc Res Tech 2004, 63(3):168-74). These structural dissimilarities result in hemostatic differences between the two materials. When compared, pGlcNAc patches induced hemostasis in 100% of cases, whereas several chitosan-based patches performed worse than a gauze pad control. (Fischer T H, Connolly R, Thatte H S, Schwaitzberg S S. Comparison of structural and hemostatic properties of the poly-N-acetyl glucosamine Syvek Patch with products containing chitosan. Microsc Res Tech 2004, 63(3):168-74).
Poly-N-acetyl glucosamine nanofibers interact with platelets, red blood cells and endothelial cells, (Thatte H S, Zagarins S, Khuri S F, Fischer T H. Mechanisms of poly-N-acetyl glucosamine polymer-mediated hemostasis: platelet interactions. J Trauma 2004; 57(1 Suppl):S13-21); (Thatte H S, Zagarins S E, Amiji M, Khuri S F. Poly-N-acetyl glucosamine-mediated red blood cell interactions. J Trauma 2004; 57(1 Suppl):S7-12) and accelerate hemostasis through a sequence of events that have been recently demonstrated. (Fischer T H, Thatte H S, Nichols T C, Bender-Neal D E, Bellinger A D, Vournakis J N. Synergistic platelet integrin signaling and factor XII activation in poly-N-acetyl glucosamine fiber-mediated hemostasis. Biomaterials 2005, 26(27):5433-43; Fischer, T. H., Valeri, C. R., Smith, C. J., Scull, C. M., Merricks, E. P., Nichols, T. P., Demcheva, M. and Vournakis, J. N. Non-classical Processes in Surface Hemostasis: Mechanisms for the Poly-N-acetyl glucosamine-induced Alteration of Red Blood Cell Morphology and Prothrombogenicity. (2008) J. Biomedical Materials Res, in press; Smith, C. J., Vournakis, J. N., Demcheva, M. and Fischer, T. H. Differential Effect of Materials for Surface Hemostasis on Red Blood Cell Morphology. (2008) Microscopic Res. Techniques, in press.)
Platelets specifically interact with the nanofibers of the pGlcNAc patch and, as a result, their activation is amplified. The activation response includes pseudopodia extension, shape change, integrin complex activation, activation of calcium signaling, phosphatidyl serine exposure on the surface membrane, binding of factor X to platelets and an acceleration of fibrin polymerization kinetics. Upon activation, platelets release vasoconstrictor substances and activate clotting after contact with the nanofibers, thus contributing to wound healing.
Therefore an appliance incorporating a hemostatic agent, preferably the hemostatic agent pGlcNac, that could be incorporated into a negative pressure wound care device such as the VAC would be highly desirable.